Axiolytics

Question 1

What are the types of anxiety disorders and their symptoms?

Answer 1

• Generalised Anxiety Disorder (GAD); Muscle tension, restlessness, irritability, sweating, insomnia, difficulty concentrating.
• Post-Traumatic Stress Disorder (PTSD).
• Panic Disorder with or without agoraphobia (palpitations, nausea, fear of dying).

Question 2

What is the difference between anxiolytics, sedatives, and hypnotics?

Answer 2

• Anxiolytics relieve anxiety and stress (ideally without sedation).
• Sedatives reduce alertness and can relieve anxiety or cause sleep at higher doses.
• Hypnotics specifically induce sleep.

Question 3

What is the principal inhibitory neurotransmitter in the mammalian CNS?

Answer 3

• Gamma-Aminobutyric Acid (GABA).
• Synthesized by decarboxylation of glutamate.
• Acts by causing hyperpolarisation via GABA A and GABA B receptors.

Question 4

How does GABA A receptor activation inhibit neurons?

Answer 4

• GABA binds to the GABA A receptor, a ligand-gated chloride ion channel.
• Allows Cl⁻ ions to enter, hyperpolarising the neuron.
• Makes the neuron less likely to depolarise and fire an action potential.

Question 5

How does serotonin (5-HT) act in the CNS?

Answer 5

• 5-HT is primarily inhibitory but has diverse roles.
• Influences sleep, mood, sensory transmission, feeding.
• Acts through multiple receptor subtypes (5-HT1 to 5-HT7).
• All are GPCRs except 5-HT3, which is a ligand-gated ion channel.

Question 6

What is the difference between synaptic and extrasynaptic GABA A receptors?

Answer 6

• Synaptic receptors detect millimolar GABA concentrations, mediate fast inhibitory postsynaptic potentials (IPSPs).
• Extrasynaptic receptors detect micromolar GABA, mediate slower IPSPs.

Question 7

What is the normal function of anxiety and when does it become pathological?

Answer 7

• Normal anxiety is a response to perceived danger activating the autonomic “fight or flight” response.
• It becomes pathological when it lacks reasonable cause and impairs normal function.

Question 8

What historical anxiolytic agents were used before benzodiazepines?

Answer 8

• Belladonna alkaloids like atropine and scopolamine (muscarinic antagonists).
• Opiates: opium, morphine, heroin.
• Bromide, chloral hydrate, urethane, thalidomide.
• Barbiturates such as amobarbital and phenobarbital (now rarely used due to side effects).

Question 9

What are the main current classes of anxiolytics?

Answer 9

• Benzodiazepines: target GABA A ionotropic receptors; used for anxiolysis, sedation, hypnosis, anticonvulsant. Examples: diazepam, temazepam, lorazepam.
• Azapirones: target presynaptic serotonin 5-HT1A GPCR receptors, e.g., buspirone, tandospirone.

Question 10

How do benzodiazepines enhance GABA A receptor function?

Answer 10

• Bind to benzodiazepine allosteric site on GABA A receptor.
• Increase receptor’s affinity for GABA.
• Potentiate inhibitory effects without directly activating receptor.

Question 11

What is the structure of the GABA A receptor?

Answer 11

• Ionotropic receptor composed of five subunits forming a chloride ion channel.
• Structurally similar to nicotinic acetylcholine receptors.
• Contains multiple binding sites for GABA and allosteric modulators.

Question 12

What are allosteric potentiators and how do they work on GABA A receptors?

Answer 12

• Molecules binding to sites other than the GABA active site.
• Do not activate receptor directly but enhance response to GABA.
• Benzodiazepines, barbiturates, and neurosteroids act as positive allosteric modulators.

Question 13

How do azapirones exert anxiolytic effects?

Answer 13

• Act as agonists or partial agonists at 5-HT1A GPCRs.
• 5HT1A receptors are mostly presynaptic, and their activation by azapirones inhibits serotonin release.
• This occurs via inhibition of adenylate cyclase, which results in a decrease of calcium.
• Calcium is required for vesicle transport, so decrease of calcium means decreased transport of vesicles and therefore decreased serotonin is released into the synapse.
• Therapeutic effects develop over 1–3 weeks, possibly via receptor desensitization.

Question 14

What are the differences in receptor targets between benzodiazepines and azapirones?

Answer 14

• Benzodiazepines modulate GABA A receptors (ionotropic chloride channels).
• Azapirones act on presynaptic serotonin 5-HT1A GPCRs to reduce serotonin release.

Question 15

What are some adverse effects of benzodiazepines and barbiturates?

Answer 15

• Sedation.
• Respiratory depression (especially with alcohol).
• Tolerance and physical dependence.
• Withdrawal symptoms (anxiety, dizziness, nausea).
• Paradoxical effects (aggression, confusion).
• Risky overdose, especially combined with alcohol/opioids.

Question 16

Why are benzodiazepines dangerous when combined with alcohol?

Answer 16

• Alcohol is an allosteric potentiator at GABA A receptors but binds at a different site than benzodiazepines.
• Combined effects can cause severe CNS and respiratory depression, increasing overdose risk.

Question 17

What are the advantages of azapirones over benzodiazepines?

Answer 17

• Fewer side effects such as sedation and dependence.
• No abuse potential.
• No cognitive impairment or memory loss.
• Slower onset and may be less effective.

Question 18

What other drugs or systems are involved in anxiolytic treatment?

Answer 18

• Antidepressants (SSRIs, SNRIs) for GAD, social anxiety, phobias, PTSD.
• Pregabalin (calcium channel blocker) for GAD, not acting on GABA.
• Beta-blockers (propranolol) for physical anxiety symptoms.
• Noradrenaline and neuropeptides (CCK, substance P) implicated but not yet targeted.

Question 19

What do UK NICE guidelines recommend for treating anxiety?

Answer 19

• Psychological therapy as first-line treatment.
• SSRIs or SNRIs as preferred pharmacological treatments.
• Benzodiazepines only for short-term acute use.
• Buspirone limited to cases poorly tolerant to SSRIs/SNRIs.

Question 20

What is the action of Buspirone?

Answer 20

• Buspirone acts as anagonist of the5HT1Areceptorwith highaffinity.
• It is a preferentialfull agonistofpresynaptic5-HT1Areceptors (inhibitoryautoreceptors), and apartial agonistofpostsynaptic5-HT1Areceptors.
• In theUnited Kingdom, buspirone is indicated only for the short-term treatment of anxiety.
• No immediate anxiolytic effects, delayedonset of action; clinical effectiveness may require 2 to 4 weeks.
• The drug has been shown to be similarly effective in the treatment of GAD tobenzodiazepinesincludingdiazepam.
• Buspirone is ineffective in the treatment of phobias or social anxiety disorder.

Question 21

What are some adverse effects of azapirones?

Answer 21

• The adverse effects of azapirones are relatively minor: principally nausea, dizziness, headaches.
• Lack abuse potential and are not addictive, do not cause cognitive/memory impairment or sedation
• Do not induce tolerance or physical dependence.
• However, azapirones are considered less effective with slow onset in controlling symptoms.